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Abstract

Background: The association between dipeptidyl-peptidase IV inhibitors (DPP-4i) and heart failure (HF) remains unclear. In 1 randomized controlled trial and some observational studies, DPP-4i reportedly increased the risk of HF, but 2 other randomized controlled trials and observational studies have shown no such risk. Here, we evaluated the risk of HF and cardiovascular outcomes of DPP-4i compared with sulfonylureas.

Methods and Results: A population-based retrospective cohort study was conducted using the Korean Health Insurance Review and Assessment Service database from January 1, 2009, to December 31, 2015. Incident users of sulfonylurea and DPP-4i who were not prescribed the comparator drug in the year before treatment initiation were included. DPP-4i–treated and sulfonylurea-treated patients were matched on propensity score, calculated with >40 variables. The risk of hospitalization for HF was evaluated with a Cox proportional hazards model in 255 691 matched pairs. Analyses were conducted in the total patient population and in both strata divided by the presence of cardiovascular disease during the baseline period. The hazard ratios (HRs) of hospitalization for HF for DPP-4i–treated patients were 0.78 (95% confidence interval [CI], 0.67–0.86) in all of the patients, 0.77 (95% CI, 0.68–0.79) in patients with baseline cardiovascular disease, and 0.71 (95% CI, 0.56–0.90) in patients without baseline cardiovascular disease compared with HRs for sulfonylurea-treated patients. Sitagliptin and linagliptin showed statistically lower risk for hospitalization for HF (HR, 0.76; 95% CI, 0.67–0.86 for sitagliptin-prescribed patients; HR, 0.74; 95% CI, 0.59–0.92 for linagliptin-prescribed patients) than for sulfonylurea. The HRs for hospitalization for myocardial infarction and stroke with the use of a DPP-4i versus sulfonylurea were HR, 0.76 (95% CI, 0.67–0.87) and HR, 0.63 (95% CI, 0.60–0.67), respectively.

Conclusions: Our findings suggest that DPP-4i use did not increase the risk of HF compared with sulfonylurea. In addition, the risks for cardiovascular outcomes were not elevated in DPP-4i–treated patients compared with sulfonylurea-treated patients.

Introduction

WHAT IS NEW?

While animal studies strongly suggest that treatment of Type 2 diabetes with dipeptidyl-peptidase IV inhibitors (DPP-4i) is protective for heart failure (HF), early clinical studies have produced conflicting data. We examined the risk of HF events in patients newly prescribed either DPP-4i or sulfonylureas using nationwide 8-year claims data.

Our data suggest that DPP-4i treatment significantly lowers future HF risk compared with sulfonylurea treatment in patients with and without pre-existing cardiovascular disease. Only 3% of patients in each group had pre-existing HF.

The risk of stroke was also lower in DPP-4i–treated patients than in sulfonylurea-treated patients, and myocardial infarction occurred less often in DPP-4i–treated patients who had pre-existing cardiovascular disease.

WHAT ARE THE CLINICAL IMPLICATIONS?

Our study suggests that DPP-4i use does not increase HF risk or other cardiovascular outcomes compared with sulfonylureas in patients with type 2 diabetes mellitus. Moreover, specific DPP-4i agents may be advantageous in these patients.

DPP-4i may be a preferred agent over sulfonylureas in the management of type 2 diabetes mellitus patients, when considering the cardiovascular risks of HF, stroke, and MI. Importantly, very few patients in this study were treated with sodium glucose co-transporter 2 inhibitors, which have also been suggested to lower HF risk.

The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. It is associated with increased risks for cardiovascular diseases (CVDs), including heart failure (HF).1 Indeed, CVDs are major causes of morbidity and mortality in T2DM patients. Thus, the American Diabetes Association and the European Association for the Study of Diabetes have recommended that practitioners consider cardiovascular outcomes as well as glucose-lowering potency when choosing a hypoglycemic agent.2

Dipeptidyl-peptidase IV inhibitors (DPP-4i) are among the most popular and effective oral antidiabetic agents because of their advantages, such as comparable glucose-lowering efficacy to other oral antidiabetic agents, low risk of hypoglycemia and weight gain, and tolerability in patients with chronic renal failure.3 However, the cardiovascular outcomes of DPP-4i have not been well established because of the relatively short duration of prescriptions, particularly for HF risk. In animal studies, there is growing evidence suggesting that DPP-4i protect against HF.4–8 In a clinical study, however, saxagliptin was associated with increased hospitalization for HF (hHF) in the phase III randomized controlled study called SAVOR-TIMI53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53) (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.07–1.51).9 In contrast to saxagliptin, sitagliptin and alogliptin did not increase hHF in the TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) and EXAMINE studies (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care), respectively.10,11 The CAROLINA study (Cardiovascular Outcome Trial of Linagliptin Versus Glimepiride in Type 2 Diabetes), which was designed to analyze the cardiovascular risk of linagliptin in a phase III randomized controlled study is still underway and is expected to be finished in 2019. Vildagliptin was not associated with increased HF risk among patients with underlying HF (New York Heart Association Class I, II, and III) in preliminary data from the Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) trial and 1 meta-analysis,12,13 but it has not yet been studied in a phase III randomized, controlled study.

Observational studies on the risk of HF in DPP-4i–treated patients have shown controversial results. Some studies have concluded that DPP-4i has a neutral effect on HF,14–16 others have shown an increased risk of HF,17,18 and still another observational study showed a protective effect against HF.19 However, the designs of these studies were limited in some specific clinical situations. Some studies involved patients who were prescribed sitagliptin only15,17,18; others had an ambiguous control group, for example, comparison with DPP-4i nonexposure group14,15,17,18 or with patients who prescribed acarbose.16 A disadvantage of previous studies is that a DPP-4i nonexposure group or placebo group was used as the control, considering that these groups also contained patients who were prescribed various oral hypoglycemic agents; the HF risk associated with DPP-4i varies depending on the proportion of patients treated with other oral hypoglycemic agents in the control group. For this reason, we selected 1 hypoglycemic agent as a control treatment instead of using a DPP-4i nonexposure group.

Sulfonylureas are one of the most frequently used second-line oral hypoglycemic agents worldwide and act on insulin secretion, similar to DPP-4i.20–23 Thus, we evaluated the HF risk of DPP-4i compared with that of sulfonylureas to assess the HF risk of DPP-4i and to assist in drug selection among second-line hypoglycemic agents. To this end, we used nationwide 8-year claim data to estimate the HF risk and cardiovascular outcomes of DPP-4i use compared with sulfonylurea. We also analyzed the effects of each DPP-4i drug (sitagliptin, saxagliptin, linagliptin, vildagliptin) on HF, compared with sulfonylurea.

Methods

Study Design

This study was a nationwide, retrospective observational cohort study. The study protocol was reviewed and approved by the Institutional Review Board of Ajou University Hospital (AJIRB-MED-EXP-16–328). The need for informed consent was waived by the Institutional Review Board because all of the data were deidentified.

Data Source

The study used the Korean Health Insurance Review and Assessment Service database, which contains comprehensive medical data, including claims of all of the outpatient, inpatient, and emergency departments, covering >99% of the South Korean population. The database contains longitudinal patient data, including patient demographics, diagnoses, drug prescriptions, and procedures. The diagnoses were coded with the International Classification of Diseases, Tenth Revision. All of the codes used are shown in Table I in the Data Supplement. Data from January 1, 2008, to December 31, 2015, were used.

Study Population and Follow-Up Period

Inclusion criteria were as follows: T2DM (International Classification of Diseases, Tenth Revision, code E11) patients aged >19 years old who were newly prescribed sulfonylurea or DPP-4i from 2009 to 2015. The first prescription date of sulfonylurea or DPP-4i was defined as the index date, and the prescribed drug was defined as the index drug. The index drug and date were designated after a 1-year washout (incident user design: both sulfonylurea-naive and DPP-4i–naive patients).24 To remove the effects of the opposing drug, patients were excluded if they had a history of ever taking both medications, regardless of duration; patients who were prescribed both medications together, patients who were first prescribed sulfonylurea and changed to DPP-4i, and patients who were first prescribed DPP-4i and changed to sulfonylurea with or without a time gap were also excluded. Patients who were admitted to a hospital for HF within 60 days before the index date were excluded. In addition, patients who had ever been diagnosed with type 1 diabetes mellitus, gestational diabetes mellitus, or polycystic ovary syndrome within the study period were excluded. The loss of samples is presented in Table II in the Data Supplement. The follow-up period started from the index date and ended at the first occurrence of the following events: cessation of index drug prescription, >30-day gap between the index drug prescriptions, or reaching the study end date (December 31, 2015).

Study Outcome

The primary outcome of the study was hHF during the study period. Secondary outcomes were hospital admission for myocardial infarction (MI), unstable angina (UA), stroke, or undergoing a percutaneous coronary intervention (PCI) or coronary artery bypass graft. Time to outcome was defined as the number of days from the index date until the first date of each primary or secondary outcome event.

Statistical Analysis

A propensity score matching approach was used to minimize the differences and various biases between sulfonylurea-treated and DPP-4i–treated patients. All of the variables in Table 1 were used for propensity score matching: age, sex, diagnoses (1 year before the index date), prescribed drugs (180 days before the index date), received procedures (1 year before the index date), hospital admission for any cause (1 year or 30 days before the index date), and cardiologist visits (1 year before the index date). In particular, β-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, aldosterone antagonists, loop diuretics, and thiazides, which may affect hHF, were also included in propensity score matching. All of the propensity score matchings were performed with the nearest neighbor technique with a caliper of 0.01 on the probability scale, and replacement of a control was not permitted. Propensity score matchings were performed a total of 3× (sulfonylurea group versus DPP-4i group in all of the patients, and either CVD stratification) with 1:1 ratio. The difference between matched pairs (sulfonylurea versus DPP-4i group) was estimated using standardized differences, and a value of ≤0.1 of the mean of the standardized difference was considered a negligible difference between groups.

To evaluate the cardiovascular effects of DPP-4i, Kaplan–Meier estimate and Cox proportional hazards model were used. Because other confounding variables were corrected for propensity score matching, the survival analysis included only outcome variables. One minus Kaplan–Meier survival approach was used in Kaplan–Meier estimate. Cox proportional hazards regression was performed in all of propensity score-matched patients at first and then in both stratifications. Finally, subgroup analyses were performed to estimate the HF risk for each DPP-4i, not as a class effect. Patients who were prescribed each DPP-4i were compared with propensity score-matched pairs who were prescribed sulfonylurea. In South Korea, sitagliptin was approved as the first DPP-4i (2008), followed by vildagliptin (2009), saxagliptin (2011), linagliptin (2012), gemigliptin (2012), and alogliptin (2014). Sitagliptin, saxagliptin, linagliptin, and vildagliptin were considered in the subgroup analysis because gemigliptin and alogliptin did not meet the statistical power calculated in a previous study.25

Results

Patient Characteristics and Follow-Up Period

In total, 761 349 patients were included in the cohort (407 685 patients in the sulfonylurea treatment group and 353 664 patients in the DPP-4i treatment group), and 910 061 person-years were considered. The number of matched patients on sulfonylurea versus DPP-4i after propensity score matching was 255 691 in both groups. The baseline characteristics of matched patients are shown in Table 1. The standardized mean difference was 0.30% (SD, 0.31%).

The mean follow-up periods of matched patients were 435.1 days. There were 1251 cases of hospital admission for HF. The numbers of matched patients with CVD were 67 765 and without CVD were 187 269 in both groups. Their baseline characteristics are presented in Table III in the Data Supplement. The standardized mean differences were 0.34% (SD, 0.47%) in matched pairs with underlying CVD and 0.31% (SD, 0.29%) in matched pairs without underlying CVD. The mean follow-up periods were 454.9 days in patients with CVD and 418.2 days in patients without CVD. In the comparison between sulfonylurea and each DPP-4i, the numbers of matched pairs were 109 176, 66 986, 36 616, and 13 632 in the sitagliptin, linagliptin, vildagliptin, and saxagliptin groups, respectively. The baseline characteristics of matched patients in each drug group are presented in Table IV in the Data Supplement. The mean follow-up periods for each comparison were 468.2 days (sulfonylurea versus sitagliptin), 468.2 days (sulfonylurea versus linagliptin), 448.6 days (sulfonylurea versus vildagliptin), and 396.4 days (sulfonylurea versus saxagliptin).

Risk of HF With DPP-4i

In total, 1251 hHF events were observed during the study period. The HRs of hHF were lower in DPP-4i than in sulfonylurea among matched groups in all of the patients and both CVD stratifications (Figure 1; HR, 0.78; 95% CI, 0.69–0.87; P<0.001 for all of the patients; HR, 0.77; 95% CI, 0.68–0.79; P<0.001 for patients with baseline CVD; and HR, 0.71; 95% CI, 0.56–0.90; P=0.004 for patients without baseline CVD). In the comparison between the sulfonylurea group and each DPP-4i drug, sitagliptin and linagliptin showed lower HRs for hHF than for sulfonylurea (Figure 2; HR, 0.76; 95% CI, 0.67–0.86; P<0.001 for sitagliptin-prescribed patients, HR, 0.74; 95% CI, 0.59–0.92; P=0.007 for linagliptin-prescribed patients). Vildagliptin and saxagliptin showed lower HRs for HF than for sulfonylurea, but the differences were not statistically significant (HR, 0.82; 95% CI, 0.62–1.08; P=0.15 for vildagliptin-prescribed patients and HR, 0.93; 95% CI, 0.57–1.54; P=0.79 for saxagliptin-prescribed patients).

Cardiovascular Outcomes of DPP-4i Therapy

The HRs for hospitalization for MI and stroke for a DPP-4i compared with sulfonylurea were 0.76 (Table 2; 95% CI, 0.67–0.87) and 0.63 (95% CI, 0.60–0.67), respectively. The risk for stroke was lower in both CVD stratifications (HR, 0.61; 95% CI, 0.59–0.69 for patients with CVD and HR, 0.57; 95% CI, 0.51–0.65 for patients without CVD). The lower HR for MI was statistically significant in patients with CVD (HR, 0.74; 95% CI, 0.62–0.88), but was not significant in patients without CVD (HR, 0.83; 95% CI, 0.68–1.004 for patients without CVD).

Discussion

This population-based retrospective cohort study showed that DPP-4i use lowered risk for hHF compared with sulfonylurea whether the patients had baseline CVD or not. Furthermore, DPP-4i use was associated with reduced cardiovascular risk, particularly for MI and stroke compared with sulfonylurea.

There have been 3 major trials revealing the association between the use of DPP-4i and cardiovascular risks. First, the SAVOR-TIMI 53 trial evaluated the cardiovascular outcome of saxagliptin by randomly assigning 16 492 patients to the saxagliptin or placebo group.9 The primary outcome was a composite of cardiovascular death, MI, or ischemic stroke, and the secondary outcome was hospitalization for UA, coronary revascularization, or HF. There were no statistically significant differences in primary outcome, hospitalization for UA, or coronary revascularization. However, patients treated with saxagliptin over 2 years had a 27% increased risk of hHF. This study has attracted worldwide interest in the HF risk of DPP-4i. However, contrary to this result, other 2 major randomized controlled trials studying sitagliptin and alogliptin showed no increased risk for hHF in the TECOS and EXAMINE studies, respectively.10,11

The results of observational studies about the HF risk of DPP-4i have been conflicting. Two observational studies showed DPP-4i use was associated with increased HF risk. One study used a nested case–control design, enrolling 7620 patients with T2DM and underlying HF.17 The primary outcome was all-cause admission or death, and the secondary outcome was hHF or all-cause death. There were 887 patients who were prescribed sitagliptin. Sitagliptin use was not associated with increased all-cause admission or death but was associated with an increased risk of hHF. However, sitagliptin use covered only 521 patient-years (average 0.58 years per patient) in this study, which was too short of a period to evaluate the effects of an oral hypoglycemic agent that could be prescribed for a lifetime. Furthermore, this study enrolled patients with underlying HF, and it cannot represent the hHF risk of DPP-4i use among T2DM patients without underlying HF. Another study used a Cox proportional hazards model with propensity score-matched pairs (DPP-4i nonexposure group versus sitagliptin group).18 The primary outcome was the first occurrence of hHF and in-hospital all-cause death, and the secondary outcome was the total number of hHF events. Sitagliptin use was associated with an increased risk of first hHF occurrence and the total hHF number, but not with in-hospital all-cause death. However, this study did not include other drugs that may affect HF, such as β-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, aldosterone antagonists, or diuretics in propensity score matching, only diabetic agents.

The observational study with the largest population conducted thus far was by the Canadian Network for Observational Drug Effect Studies.14 They conducted a nested case–control study including data from the United States, the United Kingdom, and Canadian provinces. DPP-4i treatment showed a neutral effect on hHF compared with patients who were prescribed ≥2 oral hypoglycemic agents other than DPP-4i in this study. Furthermore, Chen et al15 showed DPP-4i use had a neutral effect on hHF among T2DM patients with underlying chronic kidney disease and acute MI. They compared 205 patients who were prescribed sitagliptin with those who were prescribed a combination of drugs other than DPP-4i after propensity score matching. Subjects using any drug other than DPP-4i were used as the control group in these observational studies and randomized controlled trials. However, the HF risk of other oral hypoglycemic agents other than DPP-4i is not well established, especially for thiazolidinedione, sulfonylurea. The HF risk of DPP-4i can be evaluated differently depending on the combination of drugs in the control group. Therefore, research is underway to designate 1 oral hypoglycemic agent as a control.

Chang et al16 showed that DPP-4i had a similar HF risk as that of acarbose, which is one of the most frequently used second-line oral hypoglycemic agents in East Asia. DPP-4i use did not increase the HF risk compared with acarbose. Sulfonylurea, which is used as a second oral hypoglycemic agent worldwide, was used as a control drug for DPP-4i. DPP-4i use showed a lower risk for hHF in 2 studies when it was compared with sulfonylurea use.19,25 Fadini et al19 showed that DPP-4i use had a statistically lower HR (0.70; 95% CI, 0.52–0.94) compared with sulfonylurea use in propensity-matched patients in Italy. Fu et al25 also showed that the HR for hHF was 0.59 (95% CI, 0.38–0.89) in DPP-4i–prescribed T2DM patients without CVD in the United States compared with sulfonylurea-prescribed patients. Our results also showed that DPP-4i use was associated with a lower HR for hHF compared with sulfonylurea use in all of the patients and also in patients in both CVD stratifications. The reason for the low HRs for HF in the studies using sulfonylurea as control drug, including our study, may be because of the HF risk of sulfonylurea itself. Although the HF risk of sulfonylurea has not been well established, some studies have shown that sulfonylurea is associated with increased HF risk compared with metformin.26,27

In animal studies, DPP-4i use seems to protect against HF. Although some studies have shown positive or neutral correlations between DPP-4i administration and HF risk,28–30 there is increasing evidence of protective effects of DPP-4i against HF.4–8,31,32 DPP-4i knockout mice showed reduced cardiomyocyte hypertrophy, ventricular fibrosis, and even less aggravated left ventricular systolic pressure in the abdominal aortic banding-induced HF model,4 and DPP-4 protein expression and activity negatively correlated with left ventricular ejection fraction and diastolic function in radio frequency catheter ablation-induced HF model rats.5 Administration of sitagliptin was associated with reduced cardiomyocyte apoptosis and myocardial fibrosis,5 lower myocardial fatty acid uptake in db/db mice,6 and decreased heart rate and increased stroke volume in pacing-induced HF in nondiabetic pigs,7 and even improved survival after left anterior descending coronary artery ligation in diabetic mice.8 These findings in animal studies were consistent with our result that DPP-4i use was not associated with increased HF risk compared with sulfonylurea use.

Secondary outcome analysis showed that the risk for hospitalization because of stroke was lower in DPP-4i–treated patients than in sulfonylurea-treated patients, irrespective of baseline CVD status (HR, 0.63; 95% CI, 0.60–0.67 for patients with baseline CVD and HR, 0.64; 95% CI, 0.59–0.69 for patients without baseline CVD). The risk for hospitalization for MI was lower in total propensity score-matched patients and both CVD stratifications. These results were consistent with a previous study that showed a decreased risk of MI and stroke in DPP-4i–treated patient compared with sulfonylurea-treated patients.25 In addition, DPP-4i–treated patients had a lower risk for CVD compared with non-DPP-4i–treated patients in a study in Taiwan.33 Sulfonylurea use is known to increase the risk of cardiovascular outcomes.34–36 Our results are consistent with these previous studies.

Our study had several strengths. First, our study used the Korean Health Insurance Review and Assessment Service database, which contains ≈50 million South Koreans, covering >99% of the South Korean population for recent 8 consecutive years. Thus, it contains nearly all of the DPP-4i prescriptions to T2DM patients in South Korea. The mean follow-up period in matched patients was 435.1 days, which was longer than many other studies and provides stronger evidence about the long-term effects of these drugs on primary and secondary end points.15,16,25 Second, an incident user design was used and patients in the sulfonylurea and DPP-4i groups were mutually exclusive. We used 1-year data as the washout period to enroll only incident users, which reduced biases in retrospective nonrandomized comparative effectiveness research.24 Moreover, we excluded all of the patients who used both sulfonylurea and DPP-4i, regardless of the drug administration periods. By excluding these patients, our study removed all of the potential effects of the opposite drug. Finally, to the best of our knowledge, this is the first reported population-based cohort study on the HF risk associated with vildagliptin and linagliptin use. There are no reported double-blind, randomized control trials or population-based retrospective observational studies on the HF risk associated with vildagliptin or linagliptin. The ongoing CAROLINA study, to be completed in 2019, aims to evaluate the cardiovascular risks and outcomes of linagliptin in comparison with sulfonylurea.37 Among all DPP-4i agents, only sitagliptin has been analyzed for HF risk using a large-scale observational study design. The findings that vildagliptin and linagliptin did not increase HF risk compared with sulfonylurea will be of great utility to physicians who are concerned about using these drugs.

Our study had some limitations. First, it was a retrospective, observational study. To compensate for this, we used propensity score matching with a small caliper (0.01) with over 40 variables to reduce the bias. This design can help to minimize the difference in baseline characteristics between the groups: the standardized mean differences were 0.30%, 0.34%, and 0.31% in the matched cohorts of all of the patients, patients with CVD, and patients without CVD, respectively. Second, this study did not analyze the association between drug prescription and mortality. The Korean Health Insurance Review and Assessment Service database does not yet contain mortality data for patients. However, previous studies have shown that DPP-4i use was not associated with increased all-cause or cardiovascular death.9–11 Further studies are needed to assess the correlation between DPP-4i use and mortality in real-world settings. Third, we did not analyze matched pairs via a specified survival analysis that could account for matching. Although we did not perform a survival analysis for matched pairs, the Cox proportional hazards model may not reveal statistically significant differences with large sample sizes, compared with a stratified Cox proportional hazards model or other Cox model that accounts for matching.

In conclusion, DPP-4i use did not increase the risk of HF or CVD compared with sulfonylurea in Korean T2DM patients. Moreover, each DPP-4i (sitagliptin, linagliptin, vildagliptin, and saxagliptin) was also not associated with an increased risk of HF and sitagliptin and linagliptin even showed protective effects compared with sulfonylurea. The HRs of DPP-4i for MI and stroke were also statistically significantly low. These findings provide insights on HF and CVD risk of DPP-4i treatment compared with sulfonylurea treatment when clinicians select a second-line oral hypoglycemic agent. Further prospective randomized controlled trials using patients treated with specific oral hypoglycemic agents as the control group are needed.

Sources of Funding

This study was supported by Health Fellowship Foundation (for Y.-G. Kim); the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (for H.J. Kim, grant number NRF-2014R1A1A3050777); the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (for Y.-G. Kim, D. Yoon, S. Park, and R.W. Park, grant numbers HI16C0992 and HI14C3201). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.

; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).Diabetes Care. 2012;35:1364–1379. doi: 10.2337/dc12-0413.

. Trends in the prescription of antidiabetic medications from 2009 to 2012 in a general practice of Southern Italy: a population-based study.Diabetes Res Clin Pract. 2015;108:157–163. doi: 10.1016/j.diabres.2014.12.007.